PROJECT SUMMARY Matrix Metalloproteinases 2 and Metalloproteinase 9 (MMP2/9) have been shown to play active roles in a variety of cellular responses, including the regulation of uterine contraction. The underlying molecular mechanisms driving these effects are currently unknown. The overall objective of this proposal is to understand the mechanisms by which MMP9 promotes uterine contraction and to determine if specific inhibition of MMP9 promotes uterine quiescence. The central hypothesis is that elevation of MMP9 to levels seen in preterm patients is sufficient to increase the contractile response in human uterine tissue and drive preterm parturition. This proposal will determine if purified MMP9 promotes uterine contraction and if specific inhibition of MMP9 promotes uterine quiescence in term and preterm human uterine tissue. Experiments will be performed to determine if MMP9 inhibition can delay parturition in preterm animal models. Finally, this proposal will determine if MMP9 inhibition promotes uterine quiescence by decreasing intracellular calcium transients and apply proteomic technologies to identify novel mechanisms of MMP9 action. These data are expected to be significant because these they will provide the foundation for future experiments to determine if MMP9 or related pathway inhibitors can serve as druggable targets to promote uterine quiescence and reduce the number preterm births.